A Phase 2/3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Mavrilimumab (KPL-301) Treatment in Adult Subjects Hospitalized With Severe COVID-19 Pneumonia and Hyper-inflammation
Latest Information Update: 18 Mar 2022
At a glance
- Drugs Mavrilimumab (Primary)
- Indications COVID-19 pneumonia; Inflammation
- Focus Registrational; Therapeutic Use
- Sponsors Kiniksa Pharmaceuticals
- 16 Mar 2022 Status changed from active, no longer recruiting to completed.
- 28 Dec 2021 Phase 3 portion results presented in a Kiniksa Pharmaceuticals media release.
- 28 Dec 2021 Primary endpoint ( Proportion of Participants Alive and Free of Mechanical Ventilation at Day 29) has been not met, according to a Kiniksa Pharmaceuticals media release.
Most Recent Events
Trial Overview
Outcome
Purpose
This Phase II/III trial will evaluate Mavrilimumab for the treatment of patients with COVID-19 pneumonia and hyperinflammation.
Kiniksa's Phase 2/3 clinical trial protocol is a global, randomized, double-blind, placebo-controlled study encompassing 2 phases of development (Phase 2 and Phase 3).
The Phase 2 portion of the trial is expected to enroll approximately 160 patients and is intended to evaluate the efficacy and safety of 2 dose levels of mavrilimumab relative to placebo in patients who have tested positive for COVID-19 and have x-ray/CT evidence of bilateral pneumonia, active or recent fever, and clinical laboratory results indicative of hyper inflammation.
The Phase 3 portion is expected to enroll approximately 420 patients and is intended to confirm Phase 2 efficacy and safety findings. In both Phase 2 and Phase 3, patients are expected to be enrolled into 2 cohorts: Cohort 1 will include non-intubated, hospitalized patients who require supplemental oxygen to maintain SpO2 = 92%, (i.e., non-mechanically ventilated patients); and Cohort 2 will include hospitalized patients for whom mechanical ventilation was recently initiated within 48 hours prior to randomization (i.e., ventilated patients).
Following screening, enrolled patients in each cohort will be randomized 1:1:1 to receive a single IV infusion of mavrilimumab 6mg/kg or 10 mg/kg or placebo (Day 1). The primary efficacy endpoint for the Phase 2 portion of the trial for Cohort 1 is the proportion of patients alive and without respiratory failure (defined as the need for high flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation) at Day 15 and for Cohort 2 is the mortality rate by Day 15.
There will be a seamless transition in enrollment of patients in both cohorts between the Phase 2 and Phase 3 portions of the trial. For each cohort, once the last patient in Phase 2 is enrolled, all subsequent patients will be considered Phase 3 patients. Once the last patient in Phase 2 completes Day 15, primary efficacy and safety analyses of the Phase 2 data will be conducted. Following demonstration of efficacy and safety in Phase 2, the Phase 3 portion of the trial will be continued/completed
Primary Endpoints
Cohort 1: Proportion of subjects alive and free of mechanical ventilation at Day 29
description: Mechanical ventilation is defined as invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Mechanical ventilation status will be evaluated based on the National Institute of Allergy and Infectious Diseases (NIAID) clinical outcome 8-point ordinal scale. Subjects whose clinical outcome has met a NIAID score of 2 will be considered as using mechanical ventilation.
The NIAID is an 8-point ordinal scale of clinical outcomes: 1=death; 2=hospitalized, on invasive mechanical ventilation or ECMO; 3=hospitalized, on non-invasive ventilation or high flow oxygen devices; 4= hospitalized, requiring supplemental oxygen; 5=hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID 19 related or otherwise); 6=hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7=not hospitalized, limitation on activities and/or requiring home oxygen; 8=not hospitalized, no limitations on activities. [1]
Cohort 2: Mortality Rate at Day 29
description: Mortality rate is defined as the proportion of participants who have died by Day 29.
time_frame: Day 29
Other Endpoints
Cohort 1: Mortality rate at Day 29
description: Mortality rate is defined as the proportion of participants who die. time_frame: By Day 29
Cohort 1: Ventilation-free survival by Day 29
description: Defined as time from randomization to ventilation or death; subjects still alive will be censored at Day 29. time_frame: By Day 29
Cohort 1: Overall survival by Day 29
description: Defined as time from randomization to death; subjects still alive will be censored at Day 29. time_frame: Day 29
Cohort 2: Time to 1-point clinical improvement by Day 29
description: Defined as time from randomization to a 1-point improvement on the NIAID 8-point ordinal scale, or discharge from the hospital, whichever comes first. Subjects who die before Day 29 will be censored at Day 30. time_frame: By Day 29 [2]
Diseases Treated
| Indication | Qualifiers | Patient Segments |
|---|---|---|
| COVID-19 pneumonia | treatment | severe |
| Inflammation | treatment | - |
Subjects
- Subject Type patients
-
Number
Planned: 588
Actual: 815
- Sex male & female
- Age Group ≥ 18 years; adult; elderly
Patient Inclusion Criteria
Key - Subject (or legally authorized representative) is able and willing to provide informed consent, which includes compliance with study requirements and restrictions listed in the consent form. Consent must be performed per institutional regulations. - Age of ≥ 18 years - Positive SARS-CoV-2 (2019-nCoV) test within 14 days prior to randomization - Hospitalized for SARS-CoV-2 (2019-nCoV) - Bilateral pneumonia on chest x-ray or computed tomography - Clinical laboratory results indicative of hyper-inflammation within 7 days prior to randomization - Cohort 1: Receiving any form of non-invasive ventilation OR oxygenation to maintain SpO2 ≥ 92% and non-mechanically ventilated (examples include nasal cannula, face mask, venturi mask, high-flow nasal cannula, or non-invasive positive pressure ventilation) - Cohort 2: Recently ventilated with mechanical ventilation beginning within 48 hours prior to randomization Key
Patient Exclusion Criteria
- Onset of COVID-19 symptoms > 14 days prior to randomization - Hospitalized > 7 days prior to randomization - Need for invasive mechanical ventilation (Only for Cohort 1) - Need for ECMO - Serious prior or concomitant illness that in the opinion of the Investigator precludes the subject from enrolling in the trial - Recent treatment with cell-depleting biological therapies (eg, anti-CD20) within 12 months, non-cell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], anakinra, anti-IL-6 receptor [eg, tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer), treatment with alkylating agents within 12 weeks, treatment with cyclosporine A, azathioprine, cyclophosphamide, mycophenolate mofetil (MMF), or other immunosuppressant (except for corticosteroids) within 4 weeks prior to randomization. Medications that become standard of care for COVID-19 and/or receive emergency use authorization may be allowed after discussion with the medical monitor. - If subject is receiving or has received hydroxychloroquine within 3 months prior to screening visit, a corrected QT interval by Federicia method (QTcF) on Screening electrocardiogram (ECG) ≥500ms is exclusionary. If subject has a pacemaker, this criterion does not apply. - Enrolled in another investigational study of a medical intervention within 30 days prior to randomization. Participation in open label trials involving investigational treatments for COVID-19 may be allowed upon approval by the Sponsor. - Life expectancy less than 48 hours, in the opinion of the Investigator - Known human immunodeficiency virus infection (regardless of immunological status), known hepatitis B virus surface antigen positivity and/or anti-hepatitis C virus positivity
Trial Details
Identifiers
| Identifier | Owner |
|---|---|
| NCT04447469 | ClinicalTrials.gov: US National Institutes of Health |
| KPL301C203 | - |
Organisations
- Sponsors Kiniksa Pharmaceuticals
- Affiliations Kiniksa Pharmaceuticals
Trial Dates
-
Initiation Dates
Planned : 01 Jul 2020
Actual : 27 Jul 2020
-
Primary Completion Dates
Planned : 01 Dec 2021
Actual : 12 Nov 2021
-
End Dates
Planned : 01 Jan 2022
Actual : 14 Jan 2022
Other Details
- Design double-blind; multicentre; parallel; prospective; randomised
- Phase of Trial Phase II/III
- Location Brazil; Chile; Peru; South Africa; USA
- Focus Registrational; Therapeutic Use
Interventions
| Drugs | Route | Formulation |
|---|---|---|
| MavrilimumabPrimary Drug | Intravenous | Infusion |
10 mg/kg (Cohort 1)
Non-mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion
Drug: mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])) Other Name: (KPL-301; CAM3001)
10 mg/kg (Cohort 2)
Mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion
Drug: mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])) Other Name: (KPL-301; CAM3001)
6 mg/kg (Cohort 1)
Non-mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion
Drug: mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])) Other Name: (KPL-301; CAM3001)
6 mg/kg (Cohort 2)
Mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion
Drug: mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])) Other Name: (KPL-301; CAM3001)
Placebo (Cohort 1)
Non-mechanically ventilated participants administered placebo as a single IV infusion
Other: Placebo (matching placebo)
Placebo (Cohort 2)
Mechanically ventilated participants administered placebo as a single IV infusion
Other: Placebo (matching placebo)
Results
Therapeutic efficacy
In phase II/III study, cohort 1: 116 patients with severe COVID- 19 pneumonia and hyperinflammation, the patients received single intravenous administration of mavrilimumab (10 or 6 mg/kg) or placebo. Results demonstrated that, single infusion of mavrilimumab reduced progression to mechanical ventilation and improved survival. No differences in outcomes were observed between the 10 mg/kg and 6 mg/kg mavrilimumab arms. Mavrilimumab recipients had a reduced requirement for mechanical ventilation and improved survival. At day 29, the proportion of patients alive and free of mechanical ventilation was 12.3 percentage points higher with mavrilimumab (86.7% of patients) than placebo (74.4% of patients) (Primary endpoint; p=0.1224). Mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death through Day 29 (Hazard Ratio (HR) = 0.35; p=0.0175). Day 29 mortality was 12.5 percentage points lower in mavrilimumab recipients (8%) compared to placebo (20.5%) (p=0.0718). Patients received mavrilimumab had a 61% reduction in the risk of death through day 29 (HR= 0.39; p=0.0726). Results from phase II/III study showed that, mavrilimumab achieved primary efficacy endpoint of the proportion of patients alive and free of mechanical ventilation at Day 29. 12.3% points higher proportion of patients alive and free of mechanical ventilation in mavrilimumab (86.7%) compared with placebo (74.4%) (p=0.1224 met predefined statistical threshold of p<0.2) was observed. Patients receiving mavrilimumab demonstrated 65% reduction in in the risk of mechanical ventilation or death through Day 29 (Hazard Ratio (HR) = 0.35; p=0.0175). At day 29, 12.5% lower mortality was observed in patients receiving mavrilimumab (8%) compared with placebo recipients (20.5%) (p=0.0718). Reduction in risk of death at day 29 was 61% in mavrilimumab receiving patients (HR= 0.39; p=0.0726). Differences were not observed in the 10 mg/kg and 6mg/kg IV treatment arms. Clinical improvement was observed on top of steroids and/or antivirals [3] [1] .
Adverse events
Updated results from phase II/III showed that, mavrilimumab was safe and well tolerated. Adverse events occurred less frequently in patients received mavrilimumab as compared to placebo, which includes; secondary infections and thrombotic events (known complications of COVID-19). Thrombotic events occurred only in the placebo arm (5/40 [12.5%]). In phase II/III, mavrilimumab was well tolerated and demonstrated favorable safety profile. In placebo group, single treatment-emergent serious adverse event related to study drug was reported. Notable dose-related adverse events were not observed. In all groups including placebo, infections were observed and thrombotic events were observed in only placebo recipients [3] [1] .
Publications
-
Kiniksa Pharmaceuticals. Kiniksa Announces Positive Results for Mavrilimumab Phase 2 Trial in Non-Mechanically Ventilated Severe COVID-19 Patients. Media-Rel 2021;.
Media Release -
Pupim L, Wang TS, Hudock K, Denson J, Fourie N, Vasquez LH, et al. Mavrilimumab Improves Outcomes in Phase 2 Trial in Non-Mechanically-Ventilated Patients with Severe Covid-19 Pneumonia and Systemic Hyperinflammation. EULAR-2021 2021; abstr. LB0001.
Available from: URL: http://scientific.sparx-ip.net/archiveeular/index.cfm?c=a&view=2&item=2021LB0001 -
Kiniksa Pharmaceuticals. Kiniksa Announces Results from Phase 3 Trial of Mavrilimumab in COVID-19-Related ARDS. Media-Rel 2021;.
Media Release
Trial Centres
Investigators
| Investigator | Centre Name | Trial Centre Country |
|---|---|---|
|
Kiniksa Clinical Research Team
(781) 431-9100 clinicaltrials@kiniksa.com
show details
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|
Centres
| Centre Name | Location | Trial Centre Country |
|---|---|---|
| - |
-
|
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| Affinity Health | Oak Brook, Illinois | USA |
| Allina Health System | Minneapolis, Minnesota | USA |
| Bryn Mawr | Bryn Mawr, Pennsylvania | USA |
| Centro de Pesquisas Clínicas | Natal | Brazil |
| Clinica Las Condes | Santiago | Chile |
| Clinica Providencia | San Miguel | Peru |
| Clinica Providencia | Santiago | Chile |
| Essalud - Hospital de Emergencias Grau | Lima Cercado | Peru |
| Fundação Faculdade Regional de Medicina de São José do Rio Preto | São José | Brazil |
| Hospital Adventista de Belem | Belém | Brazil |
| Hospital Alemão Oswaldo Cruz | São Paulo | Brazil |
| Hospital Bruno Born | Lajeado | Brazil |
| Hospital Cardio Pulmonar | Salvador | Brazil |
| Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo | Ribeirão Preto | Brazil |
| Hospital Essalud Alberto Sabogal Sologuren | Bellavista | Peru |
| Hospital Nacional Cayetano Heredia | San Martín De Porres | Peru |
| IATROS International | Bloemfontein | South-Africa |
| IEP HGF - Instituto de Estudos e Pesquisas Clinicas do Ceará | Fortaleza | Brazil |
| Instituto Mário Penna | Belo Horizonte | Brazil |
| Into Research - Little Company of Mary Medical Center | Pretoria | South-Africa |
| IPECC - Instituto de Pesquisa Clínica de Campinas | Campinas | Brazil |
| Kiniksa Pharmaceuticals, Ltd. |
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| Limpopo Clinical Research Initiative | Rustenburg | South-Africa |
| Mercy Hospital | Springfield, Missouri | USA |
| Sharp Health Care | San Diego, California | USA |
| TASK Eden | George | South-Africa |
| Tiervlei Trial Center | Cape Town | South-Africa |
| Tulane Medical Center | New Orleans, Louisiana | USA |
| UCLA Medical Center | Los Angeles, California | USA |
| University of Cincinnati | Cincinnati, Ohio | USA |
| University of Texas Health Sciences | Houston, Texas | USA |
| UPECLIN - Unidade de Pesquisa Clínica | Botucatu | Brazil |
Trial History
| Event Date | Event Type | Comment |
|---|---|---|
| 18 Mar 2022 | Other trial event | Last checked against ClinicalTrials.gov record. Updated 18 Mar 2022 |
| 16 Mar 2022 | Status change - completed | Status changed from active, no longer recruiting to completed. Updated 18 Mar 2022 |
| 28 Dec 2021 | Results | Phase 3 portion results presented in a Kiniksa Pharmaceuticals media release. Updated 03 Jan 2022 |
| 28 Dec 2021 | Endpoint not met | Primary endpoint ( Proportion of Participants Alive and Free of Mechanical Ventilation at Day 29) has been not met, according to a Kiniksa Pharmaceuticals media release. Updated 03 Jan 2022 |
| 13 Dec 2021 | Completion date | Planned End Date changed from 1 Feb 2022 to 1 Jan 2022. Updated 07 Jan 2022 |
| 13 Dec 2021 | Status change - active, no longer recruiting | Status changed from recruiting to active, no longer recruiting. Updated 07 Jan 2022 |
| 03 Aug 2021 | Other trial event | According to a Kiniksa Pharmaceuticals media release, company continues to enroll non-mechanically ventilated patients in phase 3 and discontinues enrolling mechanically-ventilated patients. Updated 10 Aug 2021 |
| 08 Jun 2021 | Other trial event | According to a Kiniksa Pharmaceuticals media release, Phase 3 portion of this trial has already enrolled over 400 patients and is currently enrolling patients; data from this Phase 3 portion is expected in the first quarter of 2022. Updated 14 Jun 2021 |
| 08 Jun 2021 | Other trial event | According to a Kiniksa Pharmaceuticals media release, based upon data from the Phase 2 portion of this trial and discussions with the FDA, Kiniksa has adjusted the final sample size to appropriately power the Phase 3 portion of the clinical trial. the Phase 3 clinical trial will enroll a total of approximately 600 non-mechanically ventilated patients.. Updated 14 Jun 2021 |
| 05 Jun 2021 | Results | Results from Phase 2, Cohort 1 (n=116); assessing effect of mavrilimumab on clinical outcomes in patients hospitalized with severe COVID-19 pneumonia and systemic hyperinflammation, presented at the 22nd Annual Congress of the European League Against Rheumatism Updated 25 Jun 2021 |
| 12 Apr 2021 | Endpoint not met | Primary endpoint has not been met. (Cohort 1: Proportion of subjects alive and free of mechanical ventilation at Day 29) Updated 18 Jan 2022 |
| 12 Apr 2021 | Other trial event | According to a Kiniksa Pharmaceuticals media release, the company continues to enroll patients in the Phase 3 portion of this trial, which has already enrolled over 250 patients. Updated 22 May 2021 |
| 12 Apr 2021 | Endpoint met | Primary endpoint of proportion of Participants Alive and Free of Mechanical Ventilation at Day 29 has been met, according to a Kiniksa Pharmaceuticals media release. Updated 22 May 2021 |
| 12 Apr 2021 | Results | Results presented in a Kiniksa Pharmaceuticals media release. Updated 22 May 2021 |
| 05 Mar 2021 | Other trial event | Planned number of patients changed from 580 to 588. Updated 11 Mar 2021 |
| 05 Mar 2021 | Completion date | Planned End Date changed from 1 Apr 2021 to 1 Feb 2022. Updated 11 Mar 2021 |
| 05 Mar 2021 | Other trial event | Planned primary completion date changed from 1 Feb 2021 to 1 Dec 2021. Updated 11 Mar 2021 |
| 23 Feb 2021 | Other trial event | According to a Kiniksa Pharmaceuticals media release, the company completed enrollment in the Phase 2 portion of the trial and is enrolling patients in the Phase 3 portion. Updated 25 Feb 2021 |
| 22 Dec 2020 | Other trial event | According to a Kiniksa Pharmaceuticals media release, data from the phase 2 portion of this study is expected in the first half of 2021. Updated 31 Dec 2020 |
| 06 Oct 2020 | Other trial event | According to a Kiniksa Pharmaceuticals media release, the company is enrolling the Phase 2 portion of a global, randomized, double-blind, placebo-controlled adaptive design Phase 2/3 clinical trial. Updated 13 Oct 2020 |
| 19 Jul 2020 | Other trial event | Planned initiation date changed from 1 Jun 2020 to 1 Jul 2020. Updated 22 Jul 2020 |
| 19 Jul 2020 | Status change - recruiting | Status changed from not yet recruiting to recruiting. Updated 22 Jul 2020 |
| 29 Jun 2020 | Other trial event | New source identified and integrated ClinicalTrials.gov: (US National Institutes of Health: NCT04447469) Updated 22 Jul 2020 |
| 24 Jun 2020 | Status change - not yet recruiting | Status changed from planning to not yet recruiting. Updated 29 Jun 2020 |
| 08 Jun 2020 | Other trial event | According to a Kiniksa Pharmaceuticals media release, the company announced an active investigational new drug application (IND) with the U.S. Food and Drug Administration (FDA) for this trial. Updated 10 Jun 2020 |
| 07 Apr 2020 | New trial record | New trial record Updated 07 Apr 2020 |
| 31 Mar 2020 | Other trial event | According to a Kiniksa Pharmaceuticals media release, the company is engaging with the U.S. Food and Drug Administration (FDA) regarding the path forward for potential Phase 2/3 clinical development of mavrilimumab in COVID-19 pneumonia. Updated 07 Apr 2020 |
Table of Contents
References
-
Kiniksa Pharmaceuticals. Kiniksa Announces Positive Results for Mavrilimumab Phase 2 Trial in Non-Mechanically Ventilated Severe COVID-19 Patients. Media-Rel 2021;.
Media Release -
ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.
Available from: URL: http://clinicaltrials.gov -
Pupim L, Wang TS, Hudock K, Denson J, Fourie N, Vasquez LH, et al. Mavrilimumab Improves Outcomes in Phase 2 Trial in Non-Mechanically-Ventilated Patients with Severe Covid-19 Pneumonia and Systemic Hyperinflammation. EULAR-2021 2021; abstr. LB0001.
Available from: URL: http://scientific.sparx-ip.net/archiveeular/index.cfm?c=a&view=2&item=2021LB0001 -
Kiniksa Pharmaceuticals. Kiniksa Reports Second Quarter 2021 Financial Results and Recent Corporate and Portfolio Activity. Media-Rel 2021;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Outlines Next Steps for the Development of Mavrilimumab. Media-Rel 2021;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Announces Early Evidence of Treatment Response with Mavrilimumab in 6 Patients with Severe COVID-19 Pneumonia and Hyperinflammation. Media-Rel 2020;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Reports Fourth Quarter and Full-Year 2020 Financial Results and Corporate and Pipeline Activity. Media-Rel 2021;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Announces Data from U.S. Investigator-Initiated Study of Mavrilimumab in Severe COVID-19 Pneumonia and Hyperinflammation. Media-Rel 2020;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Announces Results from Phase 3 Trial of Mavrilimumab in COVID-19-Related ARDS. Media-Rel 2021;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Reports First Quarter 2020 Financial Results and Highlights Recent Corporate and Pipeline Activity. Media-Rel 2020;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Announces 28-Day Clinical Outcomes Data from Mavrilimumab Treatment Protocol in Severe COVID-19 Pneumonia and Active U.S. IND for Phase 2/3 Clinical Trial. Media-Rel 2020;.
Media Release -
Kiniksa Pharmaceuticals. Kiniksa Announces Positive Data from Phase 2 Trial of Mavrilimumab in Giant Cell Arteritis. Media-Rel 2020;.
Media Release
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